1. Field of the Invention
This invention is directed to compositions and methods for the use of peptides that promote neuronal migration, proliferation, survival and/or neurite outgrowth. More specifically, this invention is directed to the use of such peptides in the treatment of brain injury and neurodegenerative disease.
2. Related Art
Moderate to severe traumatic brain injury (TBI), and focal or global ischemia can result in significant neuronal cell loss and loss of brain function within a short time period after the insult. There are no treatments currently available to prevent cell death that occurs in the brain as a consequence of head injury or damage caused by disease. To date, there is also no treatment available to restore neuronal function. Treatments available at present for chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis only target symptoms. No drugs are currently available to intervene in the disease process or prevent cell death.
It is well known that cortical-subcortical non-thalamic lesions lead to apoptosis within thalamic areas 3-7 days after an insult. Retrograde thalamic degeneration is accompanied by activation of astroglia and microglia in the thalamus (Hermann et al., 2000). Non-invasive techniques like MRI reveal smaller thalamic volumes and increased ventricle-to brain ratio values within TBI patients suffering from non-thalamic structural lesions (Anderson et al., 1996). These findings indicate the high vulnerability of thalamocortical excitatory projection neurons for retrograde-triggered neuronal cell death and therefore indicate the need for a rescue strategy of injured or insulted thalamic neurons.
Functioning of the inhibitory neuronal circuits within the thalamus is crucial for intrathalamic down regulation of neuronal activity within the thalamus as well as within the striatal system. It has been shown that animals with striatal lesions similar to those that occur in Huntington's disease show an improvement in behavioural outcome when GABA-releasing polymer matrices are implanted into the thalamus (Rozas et al., 1996). On a cellular level within the striatum it has been shown that calbindin immunoreactive (“calbindin-ir”) inhibitory neurons can be rescued by administering activin A (Hughes et al., 1999).
Until now, only transplantation involving fetal striatal implants lead to an improvement or restoration of motor functions in Huntington's disease animal models (Nakao and Itakura, 2000). By restoring thalamic and striatal GABAergic systems that are impaired during Huntington's disease, improved behavioural outcome can be predicted (Beal et al., 1986).
A feature of the developing nervous system is the wide-ranging migration of precursor cells to their correct three-dimensional spatial position. These migrations promote differentiation of an array of phenotypes and the arrangement of immature neurons into the vertebrate brain. To achieve the correct wiring of approximately 100 billion neurons, construction of a cellular organisation like the formation of laminar structures in higher cortical regions is necessary (see Hatten and Heintz, 1999 for a review).
A cellular correlate for the direction of movement of a migrating neuron may be the frequency and amplitude of transient Ca2+ changes within a single migrating cell (Gomez and Spitzer, 1999) although the triggering of initiation and/or commitment of neuronal cell migration by membrane-bound or diffusible molecules remains elusive.
Many of the cues that are involved in neurite outgrowth and neuronal migration, however, have been identified. Plasma membrane molecules belonging to the integrin receptor family interact with extracellular matrix ligands, like laminin, to initiate neuronal adhesion to the substratum (Liang and Crutcher, 1992; De Curtis and Reichardt, 1993). The control of integrin expression affects a wide range of developmental and cellular processes, including the regulation of gene expression, cell adhesion, neurite outgrowth and cell migration. Other ligands which promote cell migration are cell adhesion molecules (i.e. N-CAM; cadherins; TAG-1), the laminin-like molecule netrin-1, the neuron-glial adhesion ligand astrotactin and growth or neurotrophic factors such as EGF, TGF-α, platelet activating factor and BDNF (Dodd et al., 1988; Yamamoto et al, 1990; Ishii et al., 1992; Ferri and Levitt, 1995; Ganzler and Redies, 1995).
Recently, collapsin-1 (semaphorin3A) was discovered. Collapsin-1 has chemorepulsive activities in axonal guidance and migration patterns for primary sensory neurones (Pasterkamp etal., 2000). In contrast, collapsin-1 acts as a chemoattractant for guiding cortical apical dendrites in neocortical areas (Polleux et al., 2000). Similar chemorepulsive as well as chemoattractive effects on axonal guidance are displayed by slit-1, a diffusible protein (Brose et al., 2000).
Currently, the cascade leading to the initiation of neuronal movement, namely adhesion of the neurone followed by initiation of migration, the process of migration over long distances, including turns and the migration stop signal remains to be elucidated.
Midbrain lesions with simultaneously administered TGF-α lead to a massive proliferation of multipotential stem cells originating in the subventricular zone (“SVZ”) and subsequent migration of these progenitor cells into the striatum (Fallon et al., 2000). It may be desirable, however, to activate neuronal proliferation and migration of neurons that are in close vicinity to the site of a lesion in order to prevent long-distance migration of neuronal precursors originating from the SVZ.
There is only one report featuring the chemokine stromal-derived factor (SDF-1) as a neuronal migration chemoattractant. The embryonic expression pattern of SDF-1 attracts cerebellar granule cells to migrate from the external germinal layer to the internal granular layer (Zhu et al., 2002). Nevertheless, this chemokine has no influence on postnatal tissue. There are no known migration-inducing factors that have direct chemoattractive effects on the migration behaviour of neuroblasts or neurons in adults after brain trauma or neurodegenerative disease.